1. Field of the Invention
The invention relates to a new method for the treatment of shock states, such as septic shock, cardiogenic shock, hypovolemic shock, shock caused by blood flow obstruction, neuropathic shock, and hypotensive disorders, comprising administering a pharmaceutical composition containing a guanylate cyclase inhibitor to a patient.
2. Brief Description of the Background Art
Shock is a clinical emergency, characterized by widespread, serious reduction in tissue perfusion which, if prolonged, leads to generalized impairment of cellular function. Shock is usually associated with systemic hypotension resulting from a significant decrease in either cardiac output or systemic vascular resistance, without a compensatory increase in the other.
Shock states are classified according to the precipitating factors. Examples include septic (bacteremia), cardiogenic (heart pump failure), hypovolemic (fluid loss), obstructive (circulatory obstruction), and neuropathic (drugs or spinal cord injury).
Septic shock, a life-threatening complication of bacteremia affects 150,000 to 300,000 patients annually in the United States, and has a mortality rate of 50% to 75% (Kilbourn et al., Biochem. and Biophys. Res. Comm. 172(3):1132-1138 (1990); Petros et al., The Lancet 338:1557-1558 (1991)). The shock state is characterized by circulatory insufficiency due to diffuse cell and tissue injury and the pooling of blood in the microcirculation.
The pathogenesis of the cardiovascular collapse that occurs during septic shock is poorly understood, but is believed to occur as a result of the reaction between bacterial products and components of the coagulation and complement systems. For example, bacterial endotoxin activates the synthesis and release of inflammatory mediators such as leukotrienes, prostaglandins, cytokines, such as tumor necrosis factor (TNF), and platelet activating factor. These inflammatory mediators significantly affect vasomotor tone, microvascular permeability and leukocyte and platelet aggregation.
In addition, endotoxin activates the alternative complement pathway, resulting in generation of C3a and C5a, which in turn affect platelet aggregation and vascular tone. Activation of the coagulation system by bacterial products further alters the microcirculation in tissues by contributing to thrombi formation. Finally, endotoxin stimulates release of vasoactive substance such as catecholamines, glucocorticosteroids, histamine and serotonin which, in combination, contribute to the eventual circulatory collapse.
Cardiogenic shock is the most important fatal complication of acute myocardial infarction, occurring in approximately 10% of such patients, and accounting for approximately two-thirds of in-hospital deaths. Other causes of cardiogenic shock include arrhythmias, severe congestive heart failure, mitral valve or aortic valve regurgitation, and perforation of the ventricular septum. The shock state occurs as a consequence of the decrease in arterial pressure and consequent reduction in coronary blood flow, resulting from the significant reduction in the quantity of contracting myocardium. This reduction in blood flow may further impair myocardial function, thereby increasing the size of the infarction.
Both septic and cardiogenic shock have been associated with an increase in the production of nitric oxide or endothelium-derived relaxing factor, (EDRF), a potent labile vasodilator which plays a major role in the regulation of local blood flow, vasomotor tone and systemic blood pressure through activation of soluble guanylate cyclase. In animal models of systemic shock, endotoxin and cytokines, such as interleukin-1 (IL-1) and TNF, have been shown to cause vascular relaxation and hypotension by increasing nitric oxide (NO) synthesis. In septic shock in particular, evidence suggests that TNF stimulates the production of nitric oxide by vascular endothelial cells (Lamas et al., Am. J. Physiol. 261(4 Part 1):C634-C641 (1991).
The synthesis of NO from L-arginine, occurs through the action of a constitutive enzyme in the vascular endothelium, which has a role in the physiological control of blood pressure, and an inducible NO synthase expressed throughout vessel walls in response to endotoxin or cytokines (Petros et al., Lancet 338:1557-1558 (1991)). Expression of inducible NO synthase leads to production of large quantities of NO and profound vasodilation, which is often refractory to vasoconstrictive agents. The mechanism by which NO causes vasodilation and hypotension is through activation of guanylate cyclase. This results in increased levels of cyclic GMP, which cause relaxation of smooth muscle. Thus, activation of guanylate cyclase is an important intermediary step in the NO-induced shock state.
Successful treatment of shock requires rapid restoration of cardiac output and tissue perfusion. Two groups of drugs which have been used to treat shock are beta-receptor stimulants (notably dopamine) and alpha-receptor blocking agonists (epinephrine and norepinephrine). However, all of these drugs have important disadvantages associated with their use, and in certain patients, may be ineffective in reversing established shock. Vasoconstrictive agents are often ineffective, and in patients with severe peripheral constriction, these agents may further reduce the already impaired tissue perfusion.
Effective therapy of septic shock requires immediate reversal of the cardiovascular collapse initiated by endotoxin. Because this collapse occurs as a result of complex interactions between a number of factors, treatment methods are often partially effective at best.
Recently, endotoxin-binding agents, including polymyxin B and antibodies which neutralize TNF, have been used in an attempt to modify the sequelae of septic shock. While these approaches may have prophylactic value there is no evidence that septic shock can be easily or quickly reversed by endotoxin or TNF removal (Kilbourn et al., supra 1132-1138). Some investigators indicate that NO synthase inhibitors, such as N.sup.6 -monomethyl-L-arginine (L-NMMA), may be helpful in the treatment of hypotension associated with sepsis or therapeutic use of cytokines, but caution that complete inhibition of endogenous NO synthesis may be counterproductive (Nava et al., Lancet 338:1555-1557 (1991)).
Methylene blue, a phenothiazine derivative, is a biological stain of low toxicity, as well as a guanylate cyclase inhibitor (Huang et al., Eur. J. Pharmacol. 205:289-294 (1991)). It is a member of a group of compounds, termed "redox dyes", which also includes toluidine blue and neutral red. In mice, methylene blue has been shown to decrease TNF production, when given prior to bacterial lipopolysaccharide challenge (Culo et al., Agents and Actions 34(3/4):424-428 (1991)). In addition, methylene blue has been used for the treatment of methemoglobinemia, nitrite intoxication and cyanide poisoning (Kiese et al., Eur. J. Clin. Pharmacol. 4:115-118 (1972); Burrows et al., Proc. Ann. Meet. U.S. Ani. Health Assoc. 79:266-270 (1975); and Sloand et al., Thrombi. Res. 54:677-686 (1989)).